Mem Inst Oswaldo Cruz, Rio de Janeiro, VOLUME 118 | 2023
Perspective
Anxiety, depression, and memory loss in Chagas disease: a puzzle far beyond neuroinflammation to be unpicked and solved*
1Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Biologia das Interações, Rio de Janeiro, RJ, Brasil
2Universidade Federal Fluminense, Faculdade de Medicina, Departamento de Patologia, Laboratório Multidisciplinar de Apoio à Pesquisa em Nefrologia e Ciências Médicas, Niterói, RJ, Brasil
DOI: 10.1590/0074-02760220287
ABSTRACT
Mental disorders such as anxiety, depression, and memory loss have been described in patients with chronic Chagas disease (CD), a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. Social, psychological, and biological stressors may take part in these processes. There is a consensus on the recognition of an acute nervous form of CD. In chronic CD patients, a neurological form is associated with immunosuppression and neurobehavioural changes as sequelae of stroke. The chronic nervous form of CD has been refuted, based on the absence of histopathological lesions and neuroinflammation; however, computed tomography shows brain atrophy. Overall, in preclinical models of chronic T. cruzi infection in the absence of neuroinflammation, behavioural disorders such as anxiety and depression, and memory loss are related to brain atrophy, parasite persistence, oxidative stress, and cytokine production in the central nervous system. Interferon-gamma (IFN?)-bearing microglial cells are colocalised with astrocytes carrying T. cruzi amastigote forms. In vitro studies suggest that IFN? fuels astrocyte infection by T. cruzi and implicate IFN?-stimulated infected astrocytes as sources of TNF and nitric oxide, which may also contribute to parasite persistence in the brain tissue and promote behavioural and neurocognitive changes. Preclinical trials in chronically infected mice targeting the TNF pathway or the parasite opened paths for therapeutic approaches with a beneficial impact on depression and memory loss. Despite the path taken, replicating aspects of the chronic CD and testing therapeutic schemes in preclinical models, these findings may get lost in translation as the chronic nervous form of CD does not fulfil biomedical model requirements, as the presence of neuroinflammation, to be recognised. It is hoped that brain atrophy and behavioural and neurocognitive changes are sufficient traits to bring the attention of researchers to study the biological and molecular basis of the central nervous system commitment in chronic CD.
key words:
Chagas disease
neurological disorders
behavioural changes
neurocognitive disorders
anxiety
depression
memory loss
preclinical model
benznidazole
immunotherapy
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Financial support: This work was supported by grants from FAPERJ (E-26/10.190/2018, E-26/010.101070/2018, CNE-E-26/202.572/2019), CNPq (BPP 306037/2019-0), INCTV (Grants PAEF2 and PAEF3-IOC/Fiocruz).
*This report was presented as a lecture at the I Simpósio de Neuroinfecções do IOC, Oswaldo Cruz Institute, 22nd June 2022.
+ Corresponding author: lannes@ioc.fiocruz.br / joselilannes@gmail.com 
https://orcid.org/0000-0002-1495-3027
Received 21 December 2022
Accepted 16 February 2023
